rs201477273

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP4_StrongBS1_Supporting

The NM_002693.3(POLG):c.2890C>T(p.Arg964Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,613,906 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:9B:1

Conservation

PhyloP100: 7.27

Variant links:

Genes affected

POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

POLG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.028860092).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000433 (66/152276) while in subpopulation EAS AF= 0.0108 (56/5174). AF 95% confidence interval is 0.00856. There are 1 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.2890C>T	p.Arg964Cys	missense_variant	Exon 18 of 23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 link	c.2890C>T	p.Arg964Cys	missense_variant	Exon 18 of 23		NP_001119603.1	P54098E5KNU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.2890C>T	p.Arg964Cys	missense_variant	Exon 18 of 23	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000685

AC:

172

AN:

251154

Hom.:

AF XY:

0.000575

AC XY:

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00881

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000223

AC:

326

AN:

1461630

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

144

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00599

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000811

GnomAD4 genome

AF:

0.000433

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0108

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000414

Hom.:

Bravo

AF:

0.000366

ExAC

AF:

0.000708

AC:

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2024	Reported previously in a 2 year old child with hypotonia and ataxia in whom a second POLG variant was not detected (PMID: 18546365); Published functional studies demonstrate that R964C polymerase gamma showed reduced activity in vitro compared to wild-type (PMID: 17436221, 27987238); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19364868, 20176107, 25852747, 20206271, 25462018, 19762913, 27987238, 29992832, 30941926, 31180159, 31521625, 31665838, 32165824, 32005694, 33763395, 33300680, 35314707, 35598585, 34426522, 24091540, 21880868, 17436221, 37470284, 37453004, 18546365) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 30, 2024	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. (PMID: 17436221, 19364868, 19887119, 20176107, 25462018, 27987238, 25852747, 37470284) This variant segregates with disease in multiple families. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 24, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 22, 2023	BS1, PP3, PM3, PS3 -

Progressive sclerosing poliodystrophy

Pathogenic:1Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2025	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.2890C>T (NP_002684.1:p.Arg964Cys) [GRCH38: NC_000015.10:g.89320857G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17436221 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 11, 2023	- -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM3_VeryStrong+PP4+PS3+BS1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 14, 2024	- -

Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not specified

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2024	Variant summary: POLG c.2890C>T (p.Arg964Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 251154 control chromosomes, predominantly at a frequency of 0.0088 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders phenotype. c.2890C>T has been reported in the literature in several individuals affected with clinical features of POLG-Related Spectrum Disorders without strong evidence for causality (example, Yamanaka_2007, Wong_2008, Strickler_2009, Tang_2011, Ohba_2013, Han_2019, Hu_2020, Li_2021). These report(s) do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 14% of normal polymerase gamma enzyme activity in vitro (example, Yamanaka_2007). The following publications have been ascertained in the context of this evaluation (PMID: 19364868, 31665838, 32348839, 34690748, 24091540, 19762913, 21880868, 18546365, 17436221). ClinVar contains an entry for this variant (Variation ID: 206537). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Mar 27, 2024

Criteria applied: PM3_VSTR,PS3_MOD,PP3 -

Hereditary spastic paraplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2017

- -

MELAS syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Pediatric Department, Xiangya Hospital, Central South University

This variant was observed in compound heterozygosity with variant (c.2584G>A) -

Mitochondrial DNA depletion syndrome 4b

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion, Medical Genetics

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206537, PMID:17436221, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21880868, 19762913, PM3_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17436221, 19364868, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3CNET: 0.98, PP3_P). A missense variant is a common mechanism associated with Mitochondrial DNA depletion syndrome 4B (MNGIE type) (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Spinocerebellar atrophy

Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Codex Genetics Limited

Feb 28, 2019

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2024

The p.R964C variant (also known as c.2890C>T), located in coding exon 17 of the POLG gene, results from a C to T substitution at nucleotide position 2890. The arginine at codon 964 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in two individuals who were compound heterozygotes for POLG alterations and had a clinical diagnosis of an autosomal recessive POLG-related disorder. One individual was an 8-year-old male diagnosed with mtDNA depletion syndrome, mitochondrial recessive ataxia syndrome, and progressive external ophthalmoplegia (PEO) (Ohba C et al. Neurogenetics. 2013 Nov;14(3-4):225-32). The other individual was a 17-year-old male diagnosed with ataxia neuropathy spectrum (ANS), in addition to cerebellar atrophy, and spinocerebellar ataxia with epilepsy (SCAE) (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72). The alteration is location in the polymerase domain and functional studies indicated that there was a decrease in the polymerase activity compared to wild type (Yamanaka H et al. J. Infect. Dis., 2007 May;195:1419-25; Bailey CM et al. Antimicrob. Agents Chemother., 2009 Jun;53:2610-2). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear for autosomal recessive POLG-related mitochondrial disorders; however, it is unlikely to be causative of autosomal dominant POLG-related progressive external ophthalmoplegia. -

POLG-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

The POLG c.2890C>T variant is predicted to result in the amino acid substitution p.Arg964Cys. This variant has been documented in patients with variable clinical manifestations including Parkinson disease (Hsieh et al. 2019. PubMed ID: 30941926; Kasahara et al. 2017. PubMed ID: 27987238). An in vitro study suggested that this variant may decrease nucleoside analog discrimination and impair the polymerase activity (Bailey et al. 2009. PubMed ID: 19364868). However, this variant has an allele frequency of 0.93% in Eastern Asians, including one homozygote in a large public population database, which may be too frequent to be a primary cause of disease. This variant has also been listed with conflicting interpretations from pathogenic to benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/206537/). Although we suspect that this variant may be benign, at this time, we cannot rule out the possibility that this variant may function as a hypomorphic allele, and therefore the clinical significance of this variant is currently classified as uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

.;D

MetaRNN

Benign

0.029

T;T

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.90

MVP

0.92

MPC

0.77

ClinPred

0.14

GERP RS

5.2

Varity_R

0.64

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over